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T10c12 conjugated linoleic acid (t10c12 CLA) causes the reduction of triglyceride contents in adipocytes. T10c12 CLA’s delipidation effect is associated with decreased nutrient uptake, adipogenesis, lipogenesis, and increased energy expenditure, lipolysis, fatty acid oxidation in adipocytes. However, the molecular mechanisms of CLA’s delipidation effects are still unknown. AMP-activated protein kinase (AMPK), a central regulator of cellular energy levels, is activated by an increase in the cellular AMP:ATP ratio or various cellular stresses. We demonstrated that t10c12 CLA activated AMPK in 3T3-L1 adipocytes, leading to inhibition of anabolic biosynthesis and increase of energy expenditure. Strong activation of AMPK can induce an inflammatory response, which is required for effective delipidation in t10c12 CLA-treated adipocytes. Sirtuin 1 (SIRT1), a NAD+-dependent histone/protein deacetylase that regulates energy homeostasis, is functionally required for robust TG reduction in response to t10c12 CLA in adipocytes. SIRT1 activated by t10c12 CLA is able to activate AMPK, and functions coordinately with AMPK to enhance TG loss. Activated SIRT1 is also capable of repressing peroxisome proliferator-activated receptor γ (PPARγ) activity to increase delipidation in t10c12 CLAtreated adipocytes. However, the activation of PPARγ by its agonists, essential for adipogenesis and maintenance of adipocytes, strongly reduced AMPK activity and attenuated TG loss in t10c12 CLA-treated adipocytes. T10c12 CLA also activated PPARδ, a nuclear receptor that regulates fatty acid oxidation, and PPARδ agonists and antagonists increased or decreased AMPK activity, respectively. Activated PPARδ competed more effectively for RXR, an obligate partner for many nuclear receptors, and reduced the amount of PPARγ/RXR protein complex present. Our studies define the Sirt1/AMPK/PPARγ axis as the key regulatory point for determining whether adipocytes increase or decrease TG levels, with activated SIRT1 and AMPK promoting TG loss and PPARγ opposing this loss.